US9499551B2ActiveUtilityA1
Substituted pyrrolo[2,3-b]pyridines for treating cancer or inflammatory diseases
Assignee: CONFLUENCE LIFE SCIENCES INCPriority: Jan 24, 2014Filed: Jan 23, 2015Granted: Nov 22, 2016
Est. expiryJan 24, 2034(~7.5 yrs left)· nominal 20-yr term from priority
A61P 35/04A61P 37/08A61P 37/06A61P 43/00A61P 35/00A61P 35/02A61P 25/04A61P 29/00C07D 487/04C07D 471/04A61P 17/06A61P 11/06A61K 31/4985A61K 31/437A61K 45/06A61K 2300/00A61P 1/04A61K 31/337A61P 19/02
81
PatentIndex Score
4
Cited by
13
References
10
Claims
Abstract
Disclosed herein are substituted pyrrolopyridine and pyrrolopyrazine compounds and compositions useful in the treatment of TAK mediated diseases, such as cancer, having the structure of Formula (I): wherein R 1 , R 2 , R 3 , and R 4 are as defined in the detailed description. Methods of modulation of TAK activity in a human or animal subject are also provided, providing therapeutic benefit to subjects with disease conditions, especially cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , NH(CH 2 ) n C 3-7 cycloalkyl, CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)aryl, C(O)heteroaryl, CH 2 aryl, CHFaryl, CH 2 heteroaryl, CHFheteroaryl, heterocyclyl, aryl and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, fluoro, C 1-6 alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O)C 1-6 alkylN(R 4 ) 2 , and C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen, fluoro, and CH 3 ;
each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-6 alkyl, (CH 2 ) n C 3-7 cycloalkyl, OH, OC 1-6 alkyl, OCF 3 , O-aryl, O-heteroaryl, CH 2 aryl, CH 2 heteroaryl, CH(OH)aryl, CH(OH)heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)C 1-6 alkyl, C(O)CF 3 , C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;
each R 6 is independently chosen from halo, C 1-6 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 2 F, O(CH 2 ) n CF 3 , and CN;
R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl; wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;
X is CR 7 ;
Y is chosen from a bond, CH 2 , CHF, C(O), and NHC(O); and
n is chosen from 0, 1, and 2.
2. The compound of claim 1 , wherein the compound has formula (II)
wherein:
R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)aryl, C(O)heteroaryl, CH 2 aryl, CHFaryl, CH 2 heteroaryl, CHFheteroaryl, aryl and heteroaryl;
wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, fluoro, C 1-6 alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O)C 1-6 alkylN(R 4 ) 2 , and C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen, fluoro and CH 3 ;
each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, CH 2 aryl, CH 2 heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;
each R 6 is independently chosen from halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 and CN;
R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl; wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;
Y is chosen from a bond, CH 2 , CHF, C(O), and NHC(O);
and n is chosen from 0, 1, and 2.
3. The compound of claim 2 , wherein the compound has formula (III):
wherein:
R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)aryl, C(O)heteroaryl, CH 2 aryl, CHFaryl, CH 2 heteroaryl, CHFheteroaryl, aryl and heteroaryl;
wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, fluoro, C 1-6 alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O) C1-6 alkylN(R 4 ) 2 , and C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen, fluoro and CH 3 ;
each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, CH 2 aryl, CH 2 heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;
each R 6 is independently chosen from halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 , and CN;
R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;
wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents; and
n is chosen from 0, 1, and 2.
4. The compound of claim 3 , wherein:
R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NH 2 , NHC 1-6 alkyl, N(C 1-4 alkyl) 2 , CN, aryl and heteroaryl; wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, fluoro, alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O)C 1-6 alkylN(R 4 ) 2 , C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, R 3 is chosen from hydrogen, fluoro and CH 3 ;
each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, CH 2 aryl, CH 2 heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, CN, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;
each R 6 is independently chosen from halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 and CN;
R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents; and
n is chosen from 0, 1, and 2.
5. The compound of claim 4 , wherein:
R 1 is chosen from OC 3-7 cycloalkyl, NHC 1-6 alkyl, CN, aryl and heteroaryl; wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, fluoro, alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)alkyl, C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, R 3 is chosen from hydrogen, fluoro and CH 3 ;
each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 cycloalkyl N(C 1-4 alkyl) 2 , NHC(O)alkyl, CN, trifluoromethyl, halo, aryl, and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R 5 may be optionally substituted with R 6 ;
each R 6 is independently chosen from halo, CF 3 , OCH 3 , and CN;
R 7 is chosen from hydrogen, OC 1-6 alkyl, OC 3-7 cycloalkyl, NHC 1-6 alkyl, NHC 3-7 alkyl CN, trifluoromethyl, halo, aryl and heteroaryl wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents; and
n is chosen from 0 and 1.
6. The compound of claim 1 , wherein:
R 1 is chosen from OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , NH(CH 2 ) n C 3-7 cycloalkyl, C(O)N(R 4 ) 2 , C(O)aryl, C(O)heteroaryl, CH 2 aryl, CH 2 heteroaryl, heterocyclyl, aryl and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, fluoro, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , and C(O)alkyl; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen and CH 3 ;
each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-6 alkyl, (CH 2 ) n C 3-7 cycloalkyl, OH, OC 1-6 alkyl, O-aryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)OC 1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)CF 3 , C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , aryl, and heteroaryl; wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;
each R 6 is independently chosen from halo, C 1-6 alkyl, C 3-6 cycloalkyl, CF 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 2 F, O(CH 2 ) n CF 3 , and CN;
R 7 is chosen from hydrogen, C 1-6 alkyl, and CN; wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;
X is CR 7 ;
Y is chosen from a bond, CH 2 , C(O), and NHC(O); and
n is chosen from 0, 1, and 2.
7. The compound of claim 6 , wherein:
R 1 is chosen from N(R 4 ) 2 , C(O)N(R 4 ) 2 , C(O)aryl, C(O)heteroaryl, heterocycle heterocyclyl, aryl and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;
R 2 is chosen from hydrogen, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;
R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , and C(O)alkyl; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen and CH 3 ;
each R 4 is independently chosen from hydrogen, and C 1-6 alkyl; wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;
each R 5 is independently chosen from C 1-6 alkyl, (CH 2 ) n C 3-7 cycloalkyl, OH, OC 1-6 alkyl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)OC 1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)CF 3 , C(O)aryl, C(O)heteroaryl, trifluoromethyl, halo, S(O) 2 CH 3 , aryl, and heteroaryl; wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;
each R 6 is independently chosen from halo, C 1-6 alkyl, C 3-6 cycloalkyl, CF 3 , OCH 3 , OCH 2 CH 3 , O(CH 2 ) n CF 3 , and CN;
R 7 is hydrogen;
X is CR 7 ;
Y is chosen from a bond, CH 2 , and C(O); and
n is chosen from 0, 1, and 2.
8. A compound selected from the group consisting of:
9. The compound of claim 8 , wherein the compound is selected from the group consisting of:
10. The compound of claim 9 , wherein the compound is selected from the group consisting of:Cited by (0)
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